As people strive to create complete fluidic systems in miniaturized formats, micromachining becomes more important. A broad variety of materials is available for fabricating the systems or their components, including glasses, plastics/polymers, metals, ceramics and semiconductors. To take full advantage of the available microfluidic advances, one must deal with significant additional issues, such as packaging, interfaces between components, and testing. Integrated microfluidic systems may consist of pumps, valves, channels, reservoirs, cavities, reaction chambers, mixers, heaters, fluidic interconnects, diffusers, and nozzles. Applications of microfluidic systems include chemical analysis; biological and chemical sensing; drug delivery; molecular separation; amplification, sequencing or synthesis of nucleic acids; environmental monitoring; and many others. Potential benefits include reduced size, improved performance, reduced power consumption, disposability, integration of control electronics, and lower cost.
The device body structure of the microfluidic device typically comprises an aggregation of separate parts, e.g., capillaries, joints, chambers, layers, etc., which when appropriately mated or joined together, form the microfluidic device. Typically, the microfluidic devices comprise a top portion, a bottom portion, and an interior portion. The bottom portion typically comprises a solid substrate that is substantially planar in structure with at least one substantially flat upper surface. A variety of substrate materials may be employed as the bottom portion. Typically, because the devices are microfabricated, substrate materials generally are selected based upon their compatibility with known microfabrication techniques, e.g., photolithography, wet chemical etching, laser ablation, air abrasion, techniques, injection molding, embossing, and other techniques. The substrate materials are also generally selected for their compatibility with the full range of conditions to which the microfluidic devices may be exposed, including extremes of pH, temperature, salt concentration, and application of electric fields.
Accordingly, in some preferred aspects, the substrate material may include materials normally associated with the semiconductor industry in which such microfabrication techniques are regularly employed, including, e.g., silica based substrates such as glass, quartz, silicon or polysilicon, as well as other substrate materials, such as gallium arsenide. In the case of semiconductive materials, it is often desirable to provide an insulating coating or layer, e.g., silicon oxide, over the substrate material, particularly where electric fields are to be applied.
In addition, it is known that the substrate materials will comprise polymeric materials, e.g., plastics, such as polymethylmethacrylate, polycarbonate, polytetrafluoroethylene, polyvinylchloride, polydimethysiloxane, and polysulfone. Such substrates are readily manufactured from microfabricated masters, using well-known molding techniques, such as injection molding, embossing or stamping, or by polymerizing the polymeric precursor material within the mold. Such polymeric substrate materials are preferred for their ease of manufacture, low cost and disposability, as well as their general inertness to most extreme reaction conditions. Again, these polymeric materials may include treated surfaces, e.g., derivatized or coated surfaces, to enhance their utility in the microfluidic systems, e.g., provide enhanced fluid direction.
The channels and/or chambers of the microfluidic devices are typically fabricated into the upper surfaces of the substrate, or bottom portion, using the above described microfabrication techniques, as microscale grooves or indentations. The lower surface of the top portion of the microfluidic device, which top portion typically comprises a second planar substrate, is then overlaid upon and bonded to the surface of the bottom substrate, sealing the channels and/or chambers interior portion) of the device at the interface of these two components. Bonding of the top portion to the bottom portion may be carried out using a variety of known methods, depending upon the nature of the substrate material. For example, in the case of glass substrates, thermal bonding techniques may be used which employ elevated temperatures and pressure to bond the top portion of the device to the bottom portion. Polymeric substrates may be bonded using similar techniques, except that the temperatures used are generally lower to prevent excessive melting of the substrate material. Alternative methods may be used to bond polymeric parts of the device together, including acoustic welding techniques, or the use of adhesives, e.g., UV curable adhesives.
Microfluidic systems are highly useful in medical diagnostics or drug delivery. Microfluidic delivery systems, as the microchip drug delivery devices of Santini, et al. (U.S. Pat. No. 6,123,861) and Santini, et al. (U.S. Pat. No. 5,797,898) or fluid sampling devices, must be impermeable and they must be biocompatible. The devices must not only exhibit the ability to resist the aggressive environment present in the body, but must also be compatible with both the living tissue and with the other materials of construction for the device itself. The materials are selected to avoid both galvanic and electrolytic corrosion. See U.S. Pat. Nos. 5,725,017; 5,797,898; 5,876,675; 6,123,861; and 6,154,226, each of which is incorporated in its entirety by reference herein. The digital microfluidic circuits of Cho, et al. also require compatible reservoirs to contain fluids which are processed by their novel electrowetting techniques.
In microchip drug delivery devices, the microchips control both the rate and time of release of multiple chemical substances and they control the release of a wide variety of molecules in either a continuous or a pulsed manner. A material that is impermeable to the drugs or other molecules to be delivered and that is impermeable to the surrounding fluids is used as the substrate. Reservoirs are etched into the substrate using either chemical etching or ion beam etching techniques that are well known in the field of microfabrication. Hundreds to thousands of reservoirs can be fabricated on a single microchip using these techniques.
Microfluidic systems, in addition to being highly useful in medical diagnostics, are also useful in environmental monitoring, biological food testing, chemical sensing and analysis. Current efforts on the fabrication of microfluidic systems and fluidic technologies have focused on individual component development. Components such as pumps, valves, and fluidic channels are at various stages of development. Mastrangelo, et al. (U.S. Pat. No. 6,136,212) discuss the use of protective barrier layers. U.S. Pat. No. 6,136,212, is incorporated in its entirety by reference herein
The physical properties of the release system control the rate of release of the molecules, e.g., whether the drug is in a gel or a polymer form.
The reservoirs may contain multiple drugs or other molecules in variable dosages. The filled reservoirs can be capped with materials either that degrade or that allow the molecules to diffuse passively out of the reservoir over time. They may be capped with materials that disintegrate upon application of an electric potential. Release from an active device can be controlled by a preprogrammed microprocessor, remote control, or by biosensor. Valves and pumps may also be used to control the release of the molecules.
A reservoir cap can enable passive timed release of molecules without requiring a power source, if the reservoir cap is made of materials that degrade or dissolve at a known rate or have a known permeability. The degradation, dissolution or diffusion characteristics of the cap material determine the time when release begins and perhaps the release rate.
Alternatively, the reservoir cap may enable active timed release of molecules, requiring a power source. In this case, the reservoir cap consists of a thin film of conductive material that is deposited over the reservoir, patterned to a desired geometry, and that serves as an anode. Cathodes are also fabricated on the device with their size and placement determined by the device's application and method of electrical potential control. Known conductive materials that are capable of use in active timed-release devices that dissolve into solution or form soluble compounds or ions upon the application of an electric potential, including metals, such as copper, gold, silver, and zinc and some polymers.
When an electric potential is applied between an anode and cathode, the conductive material of the anode covering the reservoir oxidizes to form soluble compounds or ions that dissolve into solution, exposing the molecules to be delivered to the surrounding fluids. Alternatively, the application of an electric potential can be used to create changes in local pH near the anode reservoir cap to allow normally insoluble ions or oxidation products to become soluble. This allows the reservoir cap to dissolve and to expose the molecules to be released to the surrounding fluids. In either case, the molecules to be delivered are released into the surrounding fluids by diffusion out of or by degradation or dissolution of the release system. The frequency of release is controlled by incorporation of a miniaturized power source and microprocessor onto the microchip.
An alternative method of drug delivery, wherein microfluidic devices are employable, involves devices for transdermal delivery or transport of therapeutic agents through iontophoresis. “lontophoresis” refers to (1) the delivery of charged drugs or molecules by electromigration, (2) the delivery of uncharged drugs or molecules by the process of electroosmosis, (3) the delivery of charged drugs or molecules by the combined processes of electromigration and electroosmosis, and/or (4) the delivery of a mixture of charged and uncharged drugs or molecules by the combined processes of electromigration and electroosmosis. See U.S. Pat. Nos. 5,681,484; 5,846,396; 6,317,629; and 6,330,471, each of which is incorporated in its entirety by reference herein.
Iontophoretic devices for delivering ionized drugs through the skin have been known since the early 1900's. Deutsch (U.S. Pat. No. 410,009 (1934)) describes an iontophoretic device that overcame disadvantages of early devices. In presently known iontophoresis devices, at least two electrodes are used. Both of these electrodes are disposed to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, agent, medicament, drug precursor or drug is delivered into the body via the skin by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery. For example, if the ionic substance to be driven into the body is negatively charged, then the negative electrode (the cathode) will be the active electrode and the positive electrode (the anode) will serve to complete the circuit.
Existing iontophoresis devices generally require a reservoir or source of the drug or other molecule, preferably an ionized or ionizable species that is to be iontophoretically delivered or introduced into the body. Such reservoirs are connected to the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired drugs or molecules.
Such iontophoresis devices may also be implanted in living tissue. Whether implanted or not, the devices must be compatible with the drugs or other molecules that they contain and must be compatible with the living tissue.
One solution to achieving biocompatibility, impermeability, and galvanic and electrolytic compatibility for an implanted device is to encase the device in a protective environment. It is well known to encase implantable devices with glass or with a covering of ceramic or metal. Davidson (U.S. Pat. No. 5,562,730), Schulman, et al. (U.S. Pat. No. 5,750,926), Cogan (U.S. Pat. No. 5,755,759) and Schulman, et al. (U.S. Pat. No. 6,259,937 B1) offer examples of this technique. See also, U.S. patent application Ser. No. 09/882,712, Publication No.: US2001/0039374 A1. U.S. Pat. Nos. 5,562,730; 5,750,926; 6,259,937 B1; and U.S. patent application Ser. No. 09/882,712, Publication No.: US2001/0039374 A1, each of the aforementioned U.S. Patents is incorporated in its entirety by reference herein.
It is known to coat microfluidic devices to increase compatibility with biological fluids (Kovacs, Micromachined Transducers Sourcebook, p 803). Kovacs reports that researchers sealed channels using a plasma-enhanced chemical vapor deposition technique to deposit amorphous, hydrogenated silicon carbide film as a deposited thin-film layer. Kovacs reports that researchers vapor-deposited an organic coating on channels to achieve compatibility with biological compounds. Cogan (U.S. Pat. No. 5,755,759) coats a biomedical device with a low permeability to water, electrically resistive thin film of amorphous silicon oxycarbide.
Santini, et al. (U.S. Pat. No. 6,123,861) discuss the technique of encapsulating a non-biocompatible material in a biocompatible material, such as poly(ethylene glycol) or polytetrafluoroethylene-like materials. They also disclose the use of silicon as a strong, non-degradable, easily etched substrate that is impermeable to the molecules to be delivered and to the surrounding living tissue. The use of silicon allows the well-developed fabrication techniques from the electronic microcircuit industry to be applied to these substrates.
It is well known, however, that silicon is dissolved when implanted in living tissue or in saline solution. Zhou, et al. report that the calculated corrosion rates are 0.005, 0.077, 0.440 and 0.690 mils per year for samples of silicon soaked in bicarbonate buffered saline at 23°, 37°, 57° and 77° C.
A method of providing microfluidic devices that are impermeable and inert to the molecules being contained therein and that resist the often hostile environments in which they are placed is needed.